Expression/activation of α5β1 integrin is linked to the β-catenin signaling pathway to drive migration in glioma cells
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Guillaume Renner1, Fanny Noulet1, Marie-Cécile Mercier1, Laurence Choulier1, Nelly Etienne-Selloum1, Jean-Pierre Gies1, Maxime Lehmann1, Isabelle Lelong-Rebel1, Sophie Martin1, Monique Dontenwill1
1UMR7213 CNRS, Team Tumoral Signaling and Therapeutic Targets, Université de Strasbourg, Faculté de Pharmacie, Illkirch, France
Monique Dontenwill, email: [email protected]
Keywords: α5β1 integrin, beta-catenin, migration, EMT, glioma
Received: April 13, 2016 Accepted: August 10, 2016 Published: August 23, 2016
The Wnt/beta catenin pathway has been highlighted as an important player of brain tumors aggressiveness and resistance to therapies. Increasing knowledges of the regulation of beta-catenin transactivation point out its hub position in different pathophysiological outcomes in glioma such as survival and migration. Crosstalks between integrins and beta-catenin pathways have been suggested in several tumor tissues. As we demonstrated earlier that α5β1 integrin may be considered as a therapeutic target in high grade glioma through its contribution to glioma cell migration and resistance to chemotherapy, we addressed here the potential relationship between α5β1 integrin and beta-catenin activation in glioma cells. We demonstrated that overexpression and activation by fibronectin of α5β1 integrin allowed the transactivation of beta-catenin gene targets included in an EMT-like program that induced an increase in cell migration. Hampering of beta catenin activation and cell migration could be similarly achieved by a specific integrin antagonist. In addition we showed that α5β1 integrin/AKT axis is mainly involved in these processes. However, blockade of beta-catenin by XAV939 (tankyrase inhibitor leading to beta-catenin degradation) did not synergize with p53 activation aiming to cell apoptosis as was the case with integrin antagonists. We therefore propose a dual implication of α5β1 integrin/AKT axis in glioma cell resistance to therapies and migration each supported by different signaling pathways. Our data thus suggest that α5β1 integrin may be added to the growing list of beta-catenin modulators and provide new evidences to assign this integrin as a valuable target to fight high grade glioma.
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